The present invention relates to a novel process for the preparation of compounds of formula I: 
wherein R1 is defined herein. The present invention also relates to the preparation of compounds of formula II: 
wherein R1 and R2 are as defined herein.
Other processes for making compounds of formula I have previously been described in International Patent Publication No. WO 98/14433, published Apr. 9, 1998, which is hereby incorporated by reference in its entirety. Previous methods employed in the art for making compounds of formula I are aryl-piperazine condensations described in Watthey et al., J. Med. Chem., 1983, 26: 1116-1122 and Reinhoudt et al., Synthesis, 1987, 641-645. These aryl-piperazine condensations employ polar aprotic solvents, such as dimethyl sulfoxide or N,N-dimethylformamide, to obtain products of formula I in about 40 to 70% yield.
The method of the present invention represents a significant advance over these previously employed methods via the use of water as a solvent. The water solvent-based reaction affords not only higher yielding reactions, but also yields higher purity product and allows for easier product isolation. Water, of course, is a much more convenient solvent from a waste management and environmental viewpoint. Compounds of formula I are intermediates in the process for making compounds of formula II.
The compounds of formula II and pharmaceutically acceptable salts thereof, also described in International Patent Publication No. WO 98/14433, produced by the use of the processes of the present invention, are useful as selective agonists and antagonists of serotonin 1 (5-HT1) receptors, specifically, of one or both of the 5-HT1A and 5-HT1D receptors. These compounds are useful in treating hypertension, all forms of depression (e.g., depression in cancer patients, depression in Parkinson""s patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, post partum depression, dysthymia; mild, moderate, or severe depressions with or without atypical features, melancholic features, psychotic features, catatonic features; seasonal affective disorder, geriatric depression, chronic depression; adjustment disorder with depressed mood or with anxiety and depressed mood; mixed anxiety and depression; substance induced mood disorder; and mood disorder secondary to a general medical condition), bipolar disorder (including in the depressed phase), generalized anxiety disorder, social anxiety, separation anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobias), posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders (e.g., binge eating disorder, anorexia nervosa and bulimia nervosa), obesity, chemical dependencies (e.g., addictions to alcohol, cocaine, heroin, phenobarbital, marijuana, nicotine and benzodiazepines), cluster headache, migraine, pain, Alzheimer""s disease, obsessive-compulsive disorder; panic disorder with and without agoraphobia; memory disorders (e.g., dementia, amnestic disorders, and age-related cognitive decline (ARCD)), Parkinson""s diseases (e.g., dementia in Parkinson""s disease, neuroleptic-induced parkinsonism and tardive dyskinesias), endocrine disorders (e.g., hyperprolactinaemia), vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal tract disorders (involving changes in motility and secretion), negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette""s syndrome, trichotillomania, kleptomania, male impotence, cancer (e.g. small cell lung carcinoma), chronic paroxysmal hemicrania, headache (associated with vascular disorders) autism, pervasive developmental disorder NOS, Asperger""s disorder, selective mutism, chronic motor or vocal tic disorder, somatization disorder, insomnia, intermittent explosive disorder, pyromania, pathological gambling, impulse-control disorder, premenstrual dysphoric disorder, and attention-deficit/hyperactivity disorder (ADHD), and other disorders for which a 5-HT1 agonist or antagonist is indicated.
The present invention relates to a process for the preparation of a compound of formula I: 
wherein R1 is (C1-C6) alkyl; comprising the step of allowing a compound of formula III: 
to react with a compound of formula IV: 
in the presence of water and a metal carbonate.
In a preferred embodiment of the invention, the molar ratio of the compound of formula IV to compound of formula III in the reaction is in the range of 1.0 to 2.0. In a more preferred embodiment, the ratio of the compound of formula IV to compound of formula III is approximately 1.8. The metal carbonate in the process of the invention is preferably an alkali metal carbonate, more preferably potassium or sodium carbonate, most preferably potassium carbonate. Preferably, the molar ratio of metal carbonate to compound of formula III is in the range of 2.0 to 1.2; more preferably, the molar ratio of the molar ratio of metal carbonate to compound of formula III is approximately 1.5. Preferably, the water volume present in the reaction is 4 ml to 30 ml per gram of 2-fluorobenzaldehyde of formula III; more preferably, 6 ml to 30 ml per gram of compound of formula III; most preferably, 8.0 ml per gram of compound of formula III.
In a preferred embodiment, the present invention relates to the process for the preparation of compounds of formula I wherein R1 is methyl, ethyl or propyl.
In a more preferred embodiment, the present invention relates to the process for the preparation of compounds of formula I wherein R1 is methyl.
The present invention further relates to a process for the preparation of the hydrochloride salt of the compound of formula I comprising reacting a compound formula I with an acyl chloride in aqueous alkanol or gaseous HCl dissolved in aqueous alkanol. Preferably, the acyl chloride is acetyl chloride and the alkanol is isopropanol.
The present invention also relates to a process for the preparation of compounds of formula II: 
wherein R1 is as defined above and R2 is xe2x80x94(CH2)mB, wherein m is zero, one, two or three and B is phenyl or naphthyl, wherein each of the foregoing phenyl and naphthyl groups may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6) alkoxy-(C1-C6)alkyl-, trifluoromethyl, trifluoromethoxy, and cyano; comprising the step of
allowing the hydrochloride salt of the compound of formula I to react in the presence of a base in a suitable solvent with a compound of formula V: 
xe2x80x83wherein R2 is as defined above.
Preferably, the base used in the process for making the compound of formula II is an alkali metal hydroxide, an alkali metal hydride, alkali metal carbonate or an alkali metal alkylamine, or alkali metal amine; more preferably, the base is sodium hydride, lithium hydride, lithium hydroxide, sodium methoxide, lithium isopropoxide, potassium t-butoxide, lithium diisopropylamide; most preferably, the base is lithium hydroxide or sodium hydride, and even further preferred, the base is the monohydrate or anhydrous lithium hydroxide. Preferably, the suitable solvent for this step is isopropanol or toluene, more preferably, toluene.
In a preferred embodiment, the present invention relates to the process for the preparation of compounds of formula II wherein R2 is phenyl optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C1-C6)alkyl, (C1-C6)alkoxy, (C1-C6) alkoxy-(C1-C6)alkyl-, trifluoromethyl, trifluoromethoxy, and cyano.
In a more preferred embodiment, the present invention relates to the process for the preparation of compounds of formula II wherein R2 is phenyl optionally substituted with one or more substituents independently selected from chloro, fluoro, bromo, or iodo.
In a most preferred embodiment, the present invention relates to the process for the preparation of compounds of formula II wherein R2 is 3,4-dichlorophenyl.
The present invention also relates to a process for the preparation of a compound of formula II: 
wherein R1 is (C1-C6) alkyl and R2 is xe2x80x94(CH2)mB, wherein m is zero, one, two or three and B is phenyl or naphthyl, wherein each of the foregoing phenyl and naphthyl groups may optionally be substituted with one or more substituents independently selected from chloro, fluoro, bromo, iodo, (C1C6)alkyl, (C1-C6)alkoxy, (C1-C6) alkoxy-(C1-C6)alkyl-, trifluoromethyl, trifluoromethoxy, and cyano; comprising the steps of
(i) allowing a compound of formula III: 
xe2x80x83to react with a compound of formula IV: 
xe2x80x83in the presence of water and a metal carbonate;
(ii) reacting the compound formula I: 
xe2x80x83wherein R1 is defined above, as formed in step (i), with an acyl chloride or gaseous hydrochloric acid dissolved in an aqueous alkanol;
(iii) reacting the hydrochloride salt of the compound of formula I formed in step (ii) in the presence of a base in a suitable solvent with a compound of formula V: 
xe2x80x83wherein R2 is defined above.
Preferably, in this three-step process, R1 is methyl and R2 is 3,4-dichlorophenyl group. In addition, it is preferred that the metal carbonate in step (i) is an alkali metal carbonate, more preferably potassium or sodium carbonate, most preferably potassium carbonate. Preferably, in step (i), the molar ratio of metal carbonate to compound of formula III is in the range of 2.0 to 1.2; more preferably, the molar ratio of the molar ratio of metal carbonate to compound of formula III is approximately 1.5.
Preferably, in step (ii), the acyl chloride is used and is preferably acetyl chloride and the alkanol is isopropanol. Preferably, in step (iii), the base used in the process for making the compound of formula II is sodium hydride, lithium hydride, lithium hydroxide, sodium methoxide, lithium isopropoxide, potassium t-butoxide, lithium diisopropylamide; most preferably, the base is lithium hydroxide or sodium hydride, and even further preferred, the base is the monohydrate or anhydrous lithium hydroxide. Preferably, the suitable solvent for this step is isopropanol or toluene, more preferably, toluene.
The present invention also relates to the preparation of the citric acid salt of a compound of formula II comprising the steps of mixing a compound of formula II and citric acid in a suitable solvent. Preferably, the suitable solvent is an (C1-C6)alkanol; more preferably, isopropanol.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d, as used herein, unless otherwise indicated, means fluorine, chlorine, bromine or iodine.
The term xe2x80x9csuitable solventxe2x80x9d, as used herein, unless otherwise indicated, means a medium which serves to largely dissolve particular indicated substance(s), compound(s) or reagent(s) to form a uniformly dispersed mixture of that substance or compound at the molecular or ionic level.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d, as used herein, unless otherwise indicated, refers to an acid addition salt of a proton acid, as defined herein, or a hydrate of an acid addition salt. The term xe2x80x9cproton acidxe2x80x9d used to prepare acid addition salts of the compounds of the process of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
xe2x80x9cTreatingxe2x80x9d refers to, and includes, reversing, alleviating, inhibiting the progress of, or preventing, a disease, disorder or condition, or one or more symptoms thereof; and, xe2x80x9ctreatmentxe2x80x9d and xe2x80x9ctherapeuticallyxe2x80x9d refer to the act of treating, as defined above.
The present invention comprises an improvement in the process for the preparation of compounds of formula I that permits the use of water as the solvent in the place of organic solvents, such as dimethyl sulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA) or N-methyl-2-pyrrolidinone (NMP), previously used to make such compounds. Unless otherwise indicated, the variables R1 and R2 are as described above. 
Referring to Scheme 1, in step (i), a compound of formula III and a compound of formula IV is allowed to react in the presence of a water-soluble base in water solvent. Preferably, a stoichiometric ratio of compound of formula IV to compound of formula III of 1.0 to 2.0, more preferably about 1.8, is used in the reaction. Preferably, the water-soluble base is a metal carbonate, more preferably an alkali metal carbonate, most preferably, potassium carbonate. Further, a stoichiometric ratio of metal carbonate to compound of formula III of 1.0 to 1.5 is preferred; more preferably, a ratio of 1.5 is used in the reaction. In addition, the water volume in the reaction is preferably between 4 and 30 ml per gram of compound of formula III; more preferably between 6 and 12 ml per gram; most preferably about 8 ml per gram. The reaction is carried out at reflux (100-105xc2x0 C.) and monitored by a technique such as HPLC until complete, then cooled and extracted with an organic solvent, such as methylene chloride. Interestingly, when compounds, such as 2-chlorobenzaldehyde or 3-fluorobenzaldehyde, are used in place of 2-fluorobenzaldehyde under the above-noted reaction conditions, these compounds remain unreacted and no addition product is detected in the reaction mixture. However, the 4-fluorobenzaldehyde compound reacts to produce a substitution product in high yield under similar conditions (See Example 2).
In Table 1 is set forth a number of reaction conditions for the process of the invention using methylpiperazine as the compound of formula IV. The highest yields are most evident from the use of sodium and potassium carbonate as the water soluble base. Based on the molar equivalents of compounds of formula III, the reaction is best carried out with 1.5 to 2.0 equivalents of methylpiperazine and about 1.5 equivalents of carbonate salt.
Step (ii) of Scheme 1 is the preparation of the hydrochloride salt of the compound of formula I (formula Ixe2x80x2). The compound of formula I is dissolved in an aqueous alkanolic solvent, preferably aqueous isopropanol, more preferably less then 5% aqueous isopropanol, most preferably 1.0% aqueous isopropanol, at ambient temperature. The acyl chloride, ((C1-C6)alkyl-COCl), preferably acetyl chloride, is added to the solution. A stoichiometric ratio of acyl chloride to compound of formula I of 1.0 to 1.5 is preferably used in this step. The reaction mixture forms a slurry and is then cooled to about 0xc2x0 C., then granulated and filtered. Alternatively, the hydrochloride salt of the compound of formula I can be prepared by dissolving approximately 1.0 equivalent of gaseous HCl in  less than 1.0% aqueous isopropanol or ethyl acetate.
Other water-soluble salts of compounds of formula I may be formed via the reaction of the compound of formula I with the acid in a suitable solvent, such as tetrahydrofuran. Although the yields are quite good, the hydrochloride salts of the compound of formula I works best in the reaction conditions designed for the preparation of compounds of formula II.

Referring to Scheme II, compounds of formula I are converted into compounds of the formula II, by subjecting them to aldol condensation conditions (step (iii)). In the aldol condensation, a compound of the formula Ixe2x80x2, the hydrochloride salt of the compound of formula I, wherein R1 is as defined above, is reacted with a compound of the formula V, where R2 is defined above, in the presence of a base. The water removal techniques may involve the use of molecular sieves or a Dean-Stark trap to isolate the water created as an azeotrope with the solvent. The aldol reaction is typically carried out in a polar solvent such as DMSO, DMF, tetrahydrofuran (THF), THF/triethylamine, isopropanol, methanol or ethanol, at a temperature from about xe2x88x9278xc2x0 C. to about 80xc2x0 C. Suitable bases for use in the aldol formation step include alkali metal hydroxides, hydrides, carbonates or alkylamines, or amines themselves, more preferably, the base used is sodium hydride, lithium hydride, lithium hydroxide, sodium methoxide, lithium isopropoxide, potassium t-butoxide, lithium diisopropylamide; most preferably, the base is lithium hydroxide or sodium hydride, and even further preferred, the base is the monohydrate or anhydrous lithium hydroxide. Preferably, the suitable solvent for this step is isopropanol or toluene, more preferably, toluene. Aldol condensations are described in xe2x80x9cModern Synthetic Reactions,xe2x80x9d Herbert O. House, 2d. Edition, W. A. Benjamin, Menlo Park, Calif., 629-682 (1972) and Tetrahedron, 38 (20), 3059 (1982).
After the aldol reaction is complete as confirmed by, e.g., TLC, HPLC, or any other suitable detection method, the reaction mixture is optimally cooled to 0-5xc2x0 C., granulated for 1 to 2 hours and then filtered. The solvent-wet cake is slurried in water and the pH adjusted to about 7-8 via addition of concentrated HCl. The slurry that forms can be cooled, granulated, and then filtered to yield the product.
As noted above, when the preferred base, lithium hydroxide monohydrate, is used, the stoichiometry can be varied in the range of 1.2 to 5.0 equivalents of lithium hydroxide to reactants, but the reaction completion times will vary. The aldol reaction appears to be catalytic in lithium hydroxide. It is noteworthy that when potassium hydroxide is used to catalyze the aldol reaction between compounds of formula Ixe2x80x2 and compounds of formula V wherein R2 is dichlorophenyl, in isopropanol, yields are significantly reduced. Potassium hydroxide appears to favor the hydrolysis of thiomorpholinone ring as the major side reaction. Once the compound of formula II is prepared, pharmaceutically acceptable acid addition salts thereof may be formed via their reaction with appropriate proton acids, particularly preferred is the citric acid addition salt of the compound of formula II.
The preparation of other compounds of the present invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
In each of the reactions discussed or illustrated in Schemes I and II above, pressure is not critical, unless otherwise indicated. Pressures from about 0.9 atmospheres to about 2 atmospheres are generally acceptable and ambient pressure, i.e., about 1 atmosphere, is preferred as a matter of convenience.
This invention is also directed to processes of the invention employing isotopically-labeled compounds identical to those recited in formula I or II, or pharmaceutically acceptable salts thereof, but for the fact that one or more atoms are replaced therein by an atom having an atomic mass or mass number different from the atomic mass or mass number usually abundantly found in nature. Examples of isotopes that can be incorporated into compounds or salts thereof of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl, respectively.
Processes using certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful, for example, in providing compounds for use in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
The activity, methods for testing activities, dosages, dosage forms, methods of administration and background information concerning the compounds of formula II are set forth in International Patent Publication No. WO 98/14433, published Apr. 9, 1998. The compounds of formula II pharmaceutically acceptable salts thereof prepared using the methods of the present invention exhibit significant agonist and antagonist activity towards the serotonin-1 receptors and are of value in the treatment of a wide variety of clinical conditions as set forth above.
The active compounds of formula II and pharmaceutically acceptable salts thereof may be administered via either oral, parenteral (e.g., intravenously, intramuscularly or subcutaneously), transdermal or topical routes to mammals. The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulfate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insulator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., depression) is 0.1 to 200 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day. Aerosol formulations for treatment of the conditions referred to above (e.g., migraine) in the average adult human are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d of aerosol contains 20 xcexcg to 1000 xcexcg of the compound of the invention. The overall daily dose with an aerosol will be within the range 100 xcexcg to 10 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
In connection with the use of an active compound of this invention with a 5-HT re-uptake inhibitor, preferably sertraline, for the treatment of subjects possessing any of the above conditions, it is to be noted that these compounds may be administered either alone or in combination with pharmaceutically acceptable carriers by either of the routes previously indicated, and that such administration can be carried out in both single and multiple dosages. More particularly, the active combination can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically-acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, aqueous suspension, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, such oral pharmaceutical formulations can be suitably sweetened and/or flavored by means of various agents of the type commonly employed for such purposes. In general, the compounds of formula I are present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage and a 5-HT re-uptake inhibitor, preferably sertraline, is present in such dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, i.e., in amounts which are sufficient to provide the desired unit dosage.
A proposed daily dose of an active compound of this invention in the combination formulation (a formulation containing an active compound of this invention and a 5-HT re-uptake inhibitor) for oral, parenteral, rectal or buccal administration to the average adult human for the treatment of the conditions referred to above is from about 0.01 mg to about 2000 mg, preferably from about 0.1 mg to about 200 mg of the active ingredient of formula I per unit dose which could be administered, for example, 1 to 4 times per day.